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Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1

Author

Listed:
  • Allen P. Zinkle

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics)

  • Mariana Bunoro Batista

    (University of Warwick, School of Life Sciences and Department of Chemistry)

  • Carmen M. Herrera

    (University of Georgia, Department of Infectious Diseases, College of Veterinary Medicine)

  • Satchal K. Erramilli

    (University of Chicago, Department of Biochemistry and Molecular Biology)

  • Brian Kloss

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics)

  • Khuram U. Ashraf

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics)

  • Kamil Nosol

    (University of Chicago, Department of Biochemistry and Molecular Biology)

  • Guozhi Zhang

    (University of Arizona, Department of Chemistry and Biochemistry)

  • Rosemary J. Cater

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
    University of Queensland, Institute for Molecular Bioscience)

  • Michael T. Marty

    (University of Arizona, Department of Chemistry and Biochemistry)

  • Anthony A. Kossiakoff

    (University of Chicago, Department of Biochemistry and Molecular Biology)

  • M. Stephen Trent

    (University of Georgia, Department of Infectious Diseases, College of Veterinary Medicine)

  • Rie Nygaard

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
    Weill Cornell Medical College, Department of Radiation Oncology)

  • Phillip J. Stansfeld

    (University of Warwick, School of Life Sciences and Department of Chemistry)

  • Filippo Mancia

    (Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics)

Abstract

Polymyxins are used to treat infections caused by multidrug-resistant Gram-negative bacteria. They are cationic peptides that target the negatively charged lipid A component of lipopolysaccharides, disrupting the outer membrane and lysing the cell. Polymyxin resistance is conferred by inner-membrane enzymes, such as phosphoethanolamine transferases, which add positively charged phosphoethanolamine to lipid A. Here, we present the structure of MCR-1, a plasmid-encoded phosphoethanolamine transferase, in its liganded form. The phosphatidylethanolamine donor substrate is bound near the active site in the periplasmic domain, and lipid A is bound over 20 Å away, within the transmembrane region. Integrating structural, biochemical, and drug-resistance data with computational analyses, we propose a two-state model in which the periplasmic domain rotates to bring the active site to lipid A, near the preferential phosphate modification site for MCR-1. This enzymatic mechanism may be generally applicable to other phosphoform transferases with large, globular soluble domains.

Suggested Citation

  • Allen P. Zinkle & Mariana Bunoro Batista & Carmen M. Herrera & Satchal K. Erramilli & Brian Kloss & Khuram U. Ashraf & Kamil Nosol & Guozhi Zhang & Rosemary J. Cater & Michael T. Marty & Anthony A. Ko, 2025. "Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65515-3
    DOI: 10.1038/s41467-025-65515-3
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